PROJECT SUMMARY Heart failure with preserved ejection fraction (HFpEF) is the fastest growing form of heart failure, is almost exclusively found in older persons and is associated with a high morbidity and mortality rate. The primary chronic symptom in HFpEF patients is severe exercise intolerance measured objectively as decreased peak exercise oxygen uptake (peak VO2). By convention, the majority of work to date has focused on central limitations, however drug therapies targeting cardiac function do not improve peak VO2 or survival in HFpEF. Emerging evidence from our group suggests that peripheral `non-cardiac' factors (e.g. decreased lean mass, impaired oxidative capacity and muscle blood flow) contribute significantly to the reduced peak VO2 in HFpEF. Exercise training is the only proven therapy to increase peak VO2 in older HFpEF patients, however the peripheral mechanisms (skeletal muscle O2 delivery/extraction, oxidative capacity) responsible for this improvement are unknown. A limitation of prior exercise training studies was the primary focus on whole body exercise which in the setting of marked increases in cardiac filling pressures and impaired cardiac output reserve?as occurs in HFpEF?may not be an optimal form of training for these patients. Exercise training modalities focused on removing the central limitation to exercise (as occurs with dynamic single-leg knee extension [KE] exercise) may prove more effective. Accordingly, the current project is dedicated to defining: a) the specific ?peripheral mechanism(s)? contributing to exercise intolerance in HFpEF, and b) specific ?peripheral? adaptations to exercise training. To achieve this objective, we will perform the first ever-direct ? measure of leg VO2, leg O2 (convective and diffusive) transport and extraction, using invasive intravascular measures and Dopper ultrasound, during maximal dynamic single-leg KE exercise in older ( 60 years) HFpEF patients with a ?primary central? phenotypye (Type A, n=40), ?primary peripheral? phenotype (Type B, n=40) and controls (n=20). Our program grant Imaging Core we will also perform the most comprehensive in vivo assessment of skeletal muscle metabolism (1H and 31P NMR spectroscopy) at rest and in response to dynamic exercise. After baseline testing, Type ?A? and ?B? HFpEF patients will be randomly assigned to two different forms of training, each which are uniquely focused on removing the central limitation to exercise (Group 1: dynamic single-leg KE exercise; or Group 2: sublingual nitroglycerin given prior to and during cycle exercise training to lower cardiac filling pressures). Given the pathophysiology of exercise intolerance and mechanisms for improvement with physical training is poorly understood, and no medications have been proven effective, our results have the potential to shift paradigms, and have a major impact on the management of older patients with HFpEF in a short-time period.